Clinical Relevance of Plasma Prostaglandin F2α Metabolite Concentrations in Patients with Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F-2 alpha (PGF(2 alpha)) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF(2 alpha) in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF(2 alpha) in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF(2 alpha), a stable metabolite of PGF(2 alpha). Methods: We measured plasma concentrations of 15-keto-dihydro PGF(2 alpha) in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF(2 alpha) concentrations with disease severity and mortality. Results: Plasma concentrations of 15-keto-dihydro PGF(2 alpha) were significantly higher in IPF patients than controls (p<0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (Rs [correlation coefficient] = -0.34, p = 0.004), forced vital capacity (Rs = -0.33, p = 0.005), diffusing capacity for carbon monoxide (Rs = -0.36, p = 0.003), the composite physiologic index (Rs = 0.40, p = 0.001), 6-minute walk distance (Rs = -0.24, p = 0.04) and end-exercise oxygen saturation (Rs = -0.25, p = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, p = 0.002) and plasma 15-keto-dihydro PGF(2 alpha) concentrations (relative risk = 1.005, p = 0.002) were independently associated with an increased risk of mortality. Conclusions: We demonstrated significant associations of plasma concentrations of PGF(2 alpha) metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF(2 alpha) in human IPF.